IL-15 superagonist N-803 improves IFNγ production and killing of leukemia and ovarian cancer cells by CD34+ progenitor-derived NK cells.

Allogeneic natural killer (NK) cell transfer is a potential immunotherapy to eliminate and control cancer. A promising source are CD34 + hematopoietic progenitor cells (HPCs), since large numbers of cytotoxic NK cells can be generated. Effective boosting of NK cell function can be achieved by interleukin (IL)-15. However, its in vivo half-life is short and potent trans-presentation by IL-15 receptor α (IL-15Rα) is absent. Therefore, ImmunityBio developed IL-15 superagonist N-803, which combines IL-15 with an activating mutation, an IL-15Rα sushi domain for trans-presentation, and IgG1-Fc for increased half-life. Here, we investigated whether and how N-803 improves HPC-NK cell functionality in leukemia and ovarian cancer (OC) models in vitro and in vivo in OC-bearing immunodeficient mice. We used flow cytometry-based assays, enzyme-linked immunosorbent assay, microscopy-based serial killing assays, and bioluminescence imaging, for in vitro and in vivo experiments. N-803 increased HPC-NK cell proliferation and interferon (IFN)γ production. On leukemia cells, co-culture with HPC-NK cells and N-803 increased ICAM-1 expression. Furthermore, N-803 improved HPC-NK cell-mediated (serial) leukemia killing. Treating OC spheroids with HPC-NK cells and N-803 increased IFNγ-induced CXCL10 secretion, and target killing after prolonged exposure. In immunodeficient mice bearing human OC, N-803 supported HPC-NK cell persistence in combination with total human immunoglobulins to prevent Fc-mediated HPC-NK cell depletion. Moreover, this combination treatment decreased tumor growth. In conclusion,  N-803 is a promising IL-15-based compound that boosts HPC-NK cell expansion and functionality in vitro and in vivo. Adding N-803 to HPC-NK cell therapy could improve cancer immunotherapy.

A randomized controlled trial to assess the effects of reimbursing the costs of smoking cessation therapy on sustained abstinence.

AIMS: We studied whether reimbursement for smoking cessation treatment (SCT) can increase prolonged abstinence from smoking up to 2 years. SETTING, PARTICIPANTS AND DESIGN: From the general population, we recruited smokers and assigned them randomly to a control group (n = 634) or an intervention group (n = 632). For 6 months, participants in the intervention group could apply for reimbursement and received information regarding the reimbursed SCT. Participants in the control group received no reimbursement or information. MEASUREMENTS: In this follow-up study, prolonged abstinence from smoking was defined as reported being abstinent from at least 7 days before the end of reimbursement until the follow-up assessment 6 months or 2 years later. FINDINGS: At 6 months after the end of reimbursement, 18 participants in the control group (2.8%) and 35 participants (5.5%) in the intervention group reported sustained abstinence for at least 6 months [odds ratio (OR) = 2.0, 95% confidence interval (CI) 1.1-3.6]. Two years after the reimbursement period, 10 participants in the control group (1.6%) and 27 participants in the intervention group (4.3%) still reported sustained abstinence (OR = 4.1, 95% CI 1.7-10.2). The overall effectiveness of SCT increased with reimbursement and was 22% in the intervention group and 8% in the control group after 2 years. CONCLUSIONS: Reimbursement may be an effective strategy to increase the prolonged abstinence rate even after 2 years.

Efficacy of bupropion and nortriptyline for smoking cessation among people at risk for or with chronic obstructive pulmonary disease.

BACKGROUND: The observations that smokers with chronic obstructive pulmonary disease (COPD) are at increased risk of depression and that nicotine may have antidepressant effects and regulate mood provide a rationale for the use of antidepressant drugs for smoking cessation in patients with COPD. No clinical trial has studied the efficacy of bupropion hydrochloride and nortriptyline hydrochloride for smoking cessation in this patient population, to our knowledge. METHODS: In a placebo-controlled double-dummy randomized trial, 255 adults at risk for COPD or with COPD were prescribed sustained-release bupropion (bupropion SR) (150 mg twice daily) or nortriptyline (75 mg once daily) for 12 weeks. All patients received smoking cessation counseling. The main outcome measure was prolonged abstinence from smoking from week 4 to week 26 after the target quit date. RESULTS: The use of bupropion SR and nortriptyline resulted in higher prolonged abstinence rates compared with placebo, although only the difference between bupropion SR and placebo was statistically significant (differences with placebo, 13.1% [95% confidence interval, 1.2%-25.1%] for bupropion SR and 10.2% [95% confidence interval, -1.7% to 22.2%] for nortriptyline). In patients with COPD, bupropion SR and nortriptyline seem efficacious in achieving prolonged abstinence (differences with placebo, 18.9% [95% confidence interval, 3.6%-34.2%] for bupropion SR and 12.9% [95% confidence interval, -0.8% to 26.4%] for nortriptyline). In participants at risk for COPD, no statistically significant differences with placebo in prolonged abstinence rates were found. CONCLUSIONS: Bupropion SR treatment is an efficacious aid to smoking cessation in patients with COPD. Nortriptyline treatment seems to be a useful alternative.

Are patients with COPD psychologically distressed?

This study was designed to assess the level of psychological distress in a heterogeneous group of patients with chronic obstructive pulmonary disease (COPD), and compare them with the general population and psychiatric outpatients. A total of 118 patients with COPD, a random sample of 500 subjects from the general population and 500 psychiatric outpatients participated in this study. The Dutch version of the Symptom Checklist-90-Revised was used to assess general psychological distress. The sample of patients with COPD experienced significantly more psychological distress than the general population and significantly less than psychiatric outpatients. Furthermore, no significant association was found between the severity of the pulmonary disease and the level of psychological distress, although patients with severe or very severe COPD appeared to be at increased risk of depression. Lastly, the pattern of psychological complaints seems comparable in depressed patients with COPD and psychiatric outpatients. Once patients with COPD report suffering from depressive symptoms, the level of distress seems to increase to that found in psychiatric outpatients. In conclusion, in clinical settings in which psychological complaints are not routinely assessed, the Beck Depression Inventory and Symptom Checklist-90-Revised are very useful for drawing attention to depression and psychological distress.

Reimbursement for smoking cessation treatment may double the abstinence rate: results of a randomized trial.

AIMS: Few smokers who try to quit smoking use smoking cessation treatment (SCT), and cost could be one factor. To increase the number of successful quitters, we assessed whether financial reimbursement for SCT would encourage the use of SCT and would as a result increase the 6-month point abstinence rate. SETTING AND PARTICIPANTS: We recruited smokers aged over 18 years from a random sample of Dutch inhabitants insured by one health insurance company. INTERVENTION AND DESIGN: The smokers were assigned randomly to the intervention group (n = 632) or control group (n = 634). Respondents in the intervention group received an offer of reimbursement for nicotine replacement therapy, bupropion and behavioural counselling. No reimbursement was offered to the control group. To preclude a change of behaviour due to disappointment in the control group, we used a randomized consent design. FINDINGS: During the reimbursement period, 10.8% smokers in the intervention group reported having used SCT compared with 4.1% in the control group (OR = 2.9, 95% CI 1.8-4.7). In the intervention group, 23.4% smokers tried to stop compared with 20.8% in the control group (OR = 1.2, 95% CI 0.9-2.4). After 6 months, the biochemically validated 7-day point prevalence abstinence rate was 5.5% in the intervention group and 2.8% in the control group (OR = 2.3, 95% CI 1.2-4.1). CONCLUSIONS: Reimbursement for SCT seems efficacious in increasing the use of SCT and may double the number of successful quitters.

Should nortriptyline be used as a first-line aid to help smokers quit? Results from a systematic review and meta-analysis.

OBJECTIVES: The objective of this paper is to evaluate the efficacy of nortriptyline for smoking cessation compared to placebo and bupropion sustained release. DATA SOURCES: Randomized trials were identified by (1) checking electronic and (2) online publicly accessible registers of clinical trials; (3) searching references of identified studies and screening abstract books of conferences and symposia, and (4) personal communication with the first authors of identified papers. REVIEW METHODS: We included randomized trials in which nortriptyline was compared to placebo or bupropion hydrochloride SR. The main clinical outcome measure was (at least) 6-month prolonged abstinence, confirmed with a biochemical test. To investigate the efficacy of nortriptyline in time, we calculated the percentage of smokers who relapsed in time. RESULTS: We identified five randomized trials, including 861 smokers. Compared to placebo medication, nortriptyline resulted in significantly higher prolonged abstinence rates after at least 6 months [relative risk (RR) = 2.4, 95% CI 1.7-3.6; RD = 0.11, 95% CI 0.07-0.15]. The difference in efficacy between nortriptyline and placebo was highest in the first months after the target quit date. However, the number of people who remained abstinent decreased substantially and significantly faster over time in the nortriptyline group. Although bupropion resulted in higher abstinence rates compared with nortriptyline, the difference was not statistically significant (RR = 1.7, 95% CI 0.7-4.1). CONCLUSION: This systematic review and meta-analysis shows that the use of nortriptyline for smoking cessation resulted in higher prolonged abstinence rates after at least 6 months compared to placebo treatment. Furthermore, the use of nortriptyline for smoking cessation is well tolerated and safe. As a result, we believe health care professionals should be recommended to prescribe nortriptyline as a first-line therapy for smoking cessation, also because of the much lower cost of nortriptyline compared to bupropion SR.

Healthcare financing systems for increasing the use of tobacco dependence treatment.

BACKGROUND: Smoking cessation treatment increases the number of successful quitters compared with unaided attempts to quit. However, only a small proportion of people who smoke take up treatment. One way to increase the use of smoking cessation treatment might be to give financial support through healthcare systems. OBJECTIVES: The primary objective of this review was to assess the effect of using healthcare financing interventions to reduce the costs of providing or using smoking cessation treatment on abstinence from smoking. SEARCH STRATEGY: Eligible studies were identified by a search of the Cochrane Tobacco Addiction group specialized register, the Cochrane Central Register of Controlled Trials (CENTRAL) Issue 3, 2003, MEDLINE (from January 1966 to August 2003) and EMBASE (from January 1980 to October 2003), screening references of relevant reviews and studies, and contacting experts in the field. SELECTION CRITERIA: We included randomized controlled trials (RCTs), controlled trials (CTs) and interrupted time series (ITS) in which the study population consisted of smokers or healthcare providers or both. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed the quality of the included studies. We calculated odds ratios (ORs) and risk differences (RDs) for the individual studies and performed meta-analysis using a random-effects model. We included economic evaluations when a study presented the costs and effects of two or more alternatives. MAIN RESULTS: Four RCTs and two CTs were directed at smokers. Five studies compared the effect of a full benefit with no benefit of which four reported the prolonged self-reported abstinence rate and showed an increase of 2% (95% confidence interval [CI] 0.00 to 0.05). The pooled OR for achieving abstinence for a period of six months was 1.48 (95% 1.17 to 1.88). Two studies directed at smokers compared a full benefit with a partial benefit and showed that the odds of being abstinent were 2.49 times higher with a full benefit (95% CI 1.59 to 3.90). The pooled RD showed a non-significant increase (RD 0.05; 95% CI -0.07 to 0.16). Only one study compared a partial benefit with no benefit and only one study was directed at healthcare providers. When a full benefit was compared with a partial or no benefit, the costs per quitter varied between $260 and $2330. AUTHORS' CONCLUSIONS: There is some evidence that healthcare financing systems directed at smokers which offer a full financial benefit can increase the self-reported prolonged abstinence rates at relatively low costs when compared with a partial or no benefit. Since there were some limitations to the methodological quality of the studies the results should be interpreted with caution. More studies are needed on the effects of healthcare financing systems directed at healthcare providers.

The efficacy of smoking cessation strategies in people with chronic obstructive pulmonary disease: results from a systematic review.

Smoking cessation is the most effective way to reduce the risk of developing chronic obstructive pulmonary disease (COPD). It prevents or delays the development of airflow limitation and also reduces its progression. The objective of this study was to systematically review the effects of interventions for smoking cessation in people with COPD. Comprehensive searches of electronic and internet databases were carried out from 1966 to March 2002, using the Cochrane Airways Group search strategy. The reference lists of all selected randomized trials and relevant reviews were inspected for additional published reports and citations of unpublished research. We evaluated the efficacy of behavioural interventions (e.g. counselling), pharmacotherapy (nicotine replacement therapy and non-nicotine therapy such as bupropion), and combinations of both. The main clinical outcome measure was prolonged abstinence after at least 6 months, confirmed by a biochemical test. Five trials comprising 6491 patients with COPD were included. Results of the Lung Health Study show that, by using an intensive behavioural (relapse prevention) programme combined with nicotine replacement therapy, prolonged abstinence rates are not only significantly higher compared with no intervention, but the difference in efficacy was sustained for over 5 years. A 12-week treatment course with bupropion sustained release combined with individual counselling, however, did not result in significantly higher prolonged abstinence rates after 12 months. Present evidence suggests that the most effective intervention for prolonged smoking cessation in patients with COPD is the combination of nicotine replacement therapy, coupled with an intensive, prolonged relapse prevention programme.

Smoking cessation for chronic obstructive pulmonary disease.

BACKGROUND: Smoking cessation is the most important treatment for smokers with chronic obstructive pulmonary disease (COPD), but little is known about the effectiveness of different smoking cessation interventions for this particular group of patients. OBJECTIVES: To determine the effectiveness of smoking cessation interventions in people with COPD. SEARCH STRATEGY: Electronic searches were undertaken on MEDLINE (from 1966 to March 2002), EMBASE (from 1989 to March 2002) and Psyclit (from 1971 to March 2002), and CENTRAL (Issue 1, 2002). SELECTION CRITERIA: Randomised controlled trials in which smoking cessation was assessed in participants with confirmed COPD. DATA COLLECTION AND ANALYSIS: Two authors extracted the data and performed the methodological quality assessment independently for each study, with disagreements resolved by consensus. High-quality was defined, based on pre-set criteria according to the DelphiList. MAIN RESULTS: Five studies were included in this systematic review, two of which were of high-quality. The high-quality studies show the effectiveness of psychosocial interventions combined with pharmacological intervention compared to no treatment: psychosocial interventions combined with nicotine replacement therapy (NRT) and a bronchodilator versus no treatment at a 5 year follow-up (RD = 0.16, 95% CI 0.14 to 0.18), (RR = 4.0, 95% CI 3.25 to 4.93), psychosocial interventions combined with NRT and placebo versus no treatment at a 5 year follow-up (RD = 0.17, 95% CI 0.14 to 0.19), (RR = 4.19, 95% CI 3.41 to 5.15). Furthermore the results show the effectiveness of various combinations of psychosocial and pharmacological interventions at a 6 months follow-up (RD = 0.07, 95% CI 0.0 to 0.13), (RR = 1.74, 95% CI 1.01 to 3.0). Unfortunately, none of the included studies compared psychosocial interventions with no treatment. Therefore we found no evidence with regard to the effectiveness of these interventions. REVIEWER'S CONCLUSIONS: Based on this systematic review, the authors found evidence that a combination of psychosocial interventions and pharmacological interventions is superior to no treatment or to psychosocial interventions alone. Furthermore we conclude that there is no clear or convincing evidence for the effectiveness of any psychosocial intervention for patients with COPD due to lack of a sufficient number of high-quality studies.

[The efficacy of smoking cessation methods available in the Netherlands: a systematic review based on Cochrane data]. / De effectiviteit van stoppen-met-rokenmethoden die in Nederland beschikbaar zijn: een systematische review op basis van Cochrane-gegevens.

OBJECTIVE: To obtain an overview of data from the Cochrane Library on smoking-cessation methods and aids available in the Netherlands. DESIGN: Systematic literature review. METHOD: Common smoking-cessation methods in the Netherlands in 1999 and 2000 were selected from previous research. Data from relevant Cochrane reviews about these cessation methods were collected, after which the efficacy was calculated as a pooled odds ratio and the effectiveness as a percentage of 12 months' continuous abstinence. RESULTS: The following methods were found to be more efficacious than placebo: tailored written advice, individual counselling, telephonic counselling, group courses, all forms of nicotine-replacement therapy, bupropion and nortriptyline. Acupuncture was not superior to placebo. It was not possible to draw any unequivocal conclusions about hypnotherapy. No randomised studies were found with respect to the 'Allen Carr method'. Rates of 12 months' continuous abstinence were as follows for those methods with proven efficacy: tailored advice: 7%, individual counselling: 16%, telephonic counselling: 7.5%, nicotine gum: 17%, nicotine patch: 13%, nicotine inhaler: 17%, nicotine tablets: 20%, bupropion: 17%, and nortriptyline: 24%. The success rates for nicotine tablets and nortriptyline were based on only 2 and 1 study respectively. CONCLUSION: Several effective smoking-cessation methods are available in the Netherlands. In trials the long-term effectiveness of these methods was between 7-24%.

Detecting patients at a high risk of developing chronic obstructive pulmonary disease in general practice: cross sectional case finding study.

OBJECTIVES: To investigate the effectiveness of case finding of patients at risk of developing chronic obstructive pulmonary disease, whether the method is suitable for use in general practice, how patients should be selected, and the time required. DESIGN: Cross sectional study. SETTING: Two semirural general practices in the Netherlands. PARTICIPANTS: 651 smokers aged 35 to 70 years. MAIN OUTCOME MEASURES: Short standardised questionnaire on bronchial symptoms for current smokers, lung function with a spirometer, and the quality of the spirometric curve. RESULTS: Of the 201 smokers not taking drugs for a pulmonary condition, 169 produced an acceptable curve (fulfilling American Thoracic Society criteria). Of these, 30 (18%, 95% confidence interval 12% to 24%) had a forced expiratory volume in one second (FEV(1)) <80% of predicted. When smokers were preselected on the basis of chronic cough, the proportion with an FEV(1) <80% of predicted increased to 27% (17 of 64; 12% to 38%). Chronic cough was a better predictor of airflow obstruction than other symptoms, such as wheeze and dyspnoea. The presence of two symptoms was a slightly better predictor than cough only (odds ratio 3.02 (1.37 to 6.64) v 2.50 (1.14 to 5.52)). Age was also a good predictor of obstruction; smokers over 60 with cough had a 48% chance of having an obstruction. The mean time needed for spirometry was four minutes. Detecting one smoker with an FEV(1) <80% of predicted cost 5 pound sterling to 10 pound sterling. CONCLUSIONS: Trained practice assistants could check all patients who smoke for chronic obstructive pulmonary disease at little cost to the practice. Cough and age are the most important predictors of the disease. By testing one smoker a day, an average practice could identify one patient at risk a week.

[Uneasiness about the safety of bupropion as an aid to smoking cessation unjustified ]. / Onrust over de veiligheid van bupropion als middel om te stoppen met roken onterecht.

A report in a national newspaper on Thursday 26 April 2001, linked the anti-smoking drug bupropion to 41 deaths. From the reports of suspected adverse reactions received by the Netherlands Pharmacovigilance Foundation, it appears that more than half the cases concerned patients at risk of developing smoking-related diseases. In 15 cases, the simultaneous use of bupropion and another antidepressant (10 patients), theophylline (1 patient) or insulin (4 patients) was reported, even though these combinations may lead to an increase in the risk of seizures. Furthermore, 2 patients were reported to have been taking anti-epileptics, despite the fact that use of bupropion is contra-indicated in patients with a seizure disorder. The results seem to illustrate that the guidelines described in the product information are not being adhered to in all cases. Provided that bupropion is used according to the guidelines in the product information, this new aid in smoking cessation is considered an effective and safe drug. It is highly unlikely that bupropion has contributed to any deaths. If prescribed appropriately and in combination with counselling (e.g. minimal intervention strategy), bupropion is as yet the most effective aid in helping people stop smoking.

[Therapies for smoking cessation (antidepressants, nicotine-replacement and counseling) and implications for the treatment of patients with chronic obstructive pulmonary disease]. / Therapieën voor stoppen met roken (antidepressiva, nicotinevervanging en counseling) en implicaties voor de behandeling van patiënten met chronische obstructieve longziekte.

Only a small percentage of smokers who state they want to stop smoking in the next half year, succeed in doing so. This is not only due to the addictive nature of smoking cigarettes, but also because of psychological and social factors. Approximately 80% of the people who have used nicotine-replacement therapy return to smoking after some time. Therefore, the interest in non-nicotine pharmacotherapy has increased considerably in recent years. The antidepressants bupropion and nortriptyline are, compared to a placebo, particularly effective smoking cessation aids (relative risk (RR)nortriptyline: 2.7; 95% CI: 1.3-5.3; RRbupropion: 1.5; 95% CI: 1.1-2.6). A combined strategy of nicotine-replacement therapy with counselling or antidepressants (bupropion or nortriptyline) with counselling, in which the physiological as well as the psychological aspects of smoking cessation are treated, seems to be the most effective. Although smoking cessation is seen as the single most important way of preventing a further deterioration of the lung function at all stages of chronic obstructive pulmonary disease (COPD), little research has been conducted amongst COPD patients. Especially the use of the antidepressants bupropion or nortriptyline seems particularly interesting for the treatment of patients with COPD. This is not only because smoking cigarettes is the major risk factor for the development of the disease, but also because COPD patients have a higher than normal prevalence of depression. Furthermore, an association has been found between smoking cigarettes and depression, and the presence of depression or depressive symptoms appears to be an important cause of relapse.